Some of the most deadly human viral infections are the result of zoonoses from other species. This makes identification of host factors that define human susceptibility to viruses currently circulating in other species an essential part of efforts to prevent and cure zoonotic infections. Host factors known to restrict cross-species transmission are some of the most rapidly evolving factors in mammalian genomes, often as a result of evolutionary 'arms races' with viruses. My research focuses uses these evolutionary signatures of gene adaptation to discover and characterize new mechanisms of innate immunity and determine how genetic variation in host immunity impacts viral transmission. My proposal focuses on the IFIT (Interferon-induced with tetratricopeptide repeat) gene family, some of the most highly upregulated genes in response to viral infection. I have found that IFITs are also among the most rapidly evolving genes in mammals, leading me to hypothesize that inter-species difference in IFIT gene repertoire and sequence will influence the success of viral transmission between species. My lab will test these hypotheses using a multidisciplinary approach that integrates insights from biochemistry, evolutionary genetics, and virology. In Aim 1, we will examine how IFIT1 evolution, both in sequence and due to gene gain and loss, influences the viruses that different hosts can restrict. In Aim 2, I will determine how a human IFIT1 functions to restrict viral replication. These studies will not only shed light on the mechanistic consequences of IFIT evolution, but will also identify species-specific changes in innate antiviral immunity. Finally, more broadly, my research will highlight the power of using an evolution-guided approach to discover and characterize factors important for cross-species viral transmission.